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Chinese Medical Journal Jun 2024Hepatic inflammatory cell accumulation and the subsequent systematic inflammation drive acute-on-chronic liver failure (ACLF) development. Previous studies showed that...
BACKGROUND
Hepatic inflammatory cell accumulation and the subsequent systematic inflammation drive acute-on-chronic liver failure (ACLF) development. Previous studies showed that the vagus nerve exerts anti-inflammatory activity in many inflammatory diseases. Here, we aimed to identify the key molecule mediating the inflammatory process in ACLF and reveal the neuroimmune communication arising from the vagus nerve and immunological disorders of ACLF.
METHODS
Proteomic analysis was performed and validated in ACLF model mice or patients, and intervention animal experiments were conducted using neutralizing antibodies. PNU-282987 (acetylcholine receptor agonist) and vagotomy were applied for perturbing vagus nerve activity. Single-cell RNA sequencing (scRNA-seq), flow cytometry, immunohistochemical and immunofluorescence staining, and CRISPR/Cas9 technology were used for in vivo or in vitro mechanistic studies.
RESULTS
The unbiased proteomics identified C-X-C motif chemokine ligand 9 (CXCL9) as the greatest differential protein in the livers of mice with ACLF and its relation to the systematic inflammation and mortality were confirmed in patients with ACLF. Interventions on CXCL9 and its receptor C-X-C chemokine receptor 3 (CXCR3) improved liver injury and decreased mortality of ACLF mice, which were related to the suppressing of hepatic immune cells' accumulation and activation. Vagus nerve stimulation attenuated while vagotomy aggravated the expression of CXCL9 and the severity of ACLF. Blocking CXCL9 and CXCR3 ameliorated liver inflammation and increased ACLF-associated mortality in ACLF mice with vagotomy. scRNA-seq revealed that hepatic macrophages served as the major source of CXCL9 in ACLF and were validated by immunofluorescence staining and flow cytometry analysis. Notably, the expression of CXCL9 in macrophages was modulated by vagus nerve-mediated cholinergic signaling.
CONCLUSIONS
Our novel findings highlighted that the neuroimmune communication of the vagus nerve-macrophage-CXCL9 axis contributed to ACLF development. These results provided evidence for neuromodulation as a promising approach for preventing and treating ACLF.
PubMed: 38945689
DOI: 10.1097/CM9.0000000000003104 -
Metabolism: Clinical and Experimental Oct 2022Bariatric-metabolic surgery (BMS) in patients with obesity frequently leads to remission of concurrent type 2 diabetes mellitus (T2DM), even before body weight loss...
Bariatric-metabolic surgery (BMS) in patients with obesity frequently leads to remission of concurrent type 2 diabetes mellitus (T2DM), even before body weight loss takes place. This is probably based on the correction of a dysmetabolic cycle in the gastrointestinal physiology of T2DM that includes increased vagus-dependent exocrine pancreatic secretion (EPS) and, hence, amplified digestion and nutrient absorption. The resultant chronic exposure of tissues to high plasma levels of glucose, fatty acids and amino acids causes tissue resistance to the actions of insulin and, at a later stage, β-cell dysfunction and reduction of insulin release. We hypothesize that the addition of a surgical truncal vagotomy (TV) may improve and solidify the beneficial results of BMS on T2DM by stably decreasing EPS, - hence reducing the digestion and absorption of nutrients -, and increasing incretin secretion as a result of increased delivery of unabsorbed nutrients to the distal intestine. This hypothesis is supported by surgical data from gastrointestinal malignancies and peptic ulcer operations that include TV, as well as by vagal blockade studies. We suggest that TV may result in a stable reduction of EPS, and that its combination with the appropriate type of BΜS, may enhance and sustain the salutary effects of the latter on T2DM.
Topics: Bariatric Surgery; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Vagotomy, Truncal
PubMed: 35835160
DOI: 10.1016/j.metabol.2022.155263 -
Addiction Biology Mar 2022Previous studies showed that vagotomy markedly inhibits alcohol self-administration. Present studies hypothesised that vagotomy significantly adds to the inhibition of...
Previous studies showed that vagotomy markedly inhibits alcohol self-administration. Present studies hypothesised that vagotomy significantly adds to the inhibition of alcohol relapse induced by drugs that reduce the alcohol-induced hyperglutamatergic state (e.g., N-acetylcysteine + acetylsalicylic acid). The alcohol relapse paradigm tested gauges the elevated alcohol intake observed in animals that had consumed ethanol chronically, were subjected to a prolonged alcohol deprivation and are subsequently allowed ethanol re-access. Ethanol-drinker rats (UChB) were exposed to 10% and 20% ethanol and water concurrently for 4 months, were alcohol deprived for 14 days and were thereafter allowed re-access to the ethanol solutions. An initial binge-like drinking episode is observed upon ethanol re-access, followed by a protracted elevated ethanol intake that exceeds the predeprivation intake baseline. Prior to ethanol re-access, animals were (i) administered N-acetylcysteine (40 mg/kg/day) + acetylsalicylic acid (15 mg/kg/day), (ii) were bilaterally vagotomised, (iii) were exposed to both treatments or (iv) received no treatments. The initial binge-like relapse intake and a protracted elevated ethanol intake observed after repeated ethanol deprivations/re-access cycles were inhibited by 50%-70% by the administration of N-acetylcysteine + acetylsalicylic acid and by 40%-70% by vagotomy, while the combined vagotomy plus N-acetylcysteine + acetylsalicylic acid treatment inhibited both the initial binge-like intake and the protracted ethanol intake by >95% (p < 0.001), disclosing a dual mechanism of ethanol relapse and subsequent inhibition beyond that induced by either treatment alone. Future exploration into the mechanism by which vagal activity contributes to ethanol relapse may have translational promise.
Topics: Alcohol Drinking; Animals; Chronic Disease; Ethanol; Rats; Recurrence; Self Administration
PubMed: 35229957
DOI: 10.1111/adb.13140 -
Brain Stimulation 2023Vagus nerve stimulation (VNS) exerts neuroprotective and anti-inflammatory effects in preclinical models of central nervous system disorders, including Parkinson's...
Continuous vagus nerve stimulation exerts beneficial effects on rats with experimentally induced Parkinson's disease: Evidence suggesting involvement of a vagal afferent pathway.
BACKGROUND
Vagus nerve stimulation (VNS) exerts neuroprotective and anti-inflammatory effects in preclinical models of central nervous system disorders, including Parkinson's disease (PD). VNS setting applied for experimental models is limited into single-time or intermittent short-duration stimulation. We developed a VNS device which could deliver continuous stimulation for rats. To date, the effects of vagal afferent- or efferent-selective stimulation on PD using continuous electrical stimulation remains to be determined.
OBJECTIVE
To investigate the effects of continuous and selective stimulation of vagal afferent or efferent fiber on Parkinsonian rats.
METHODS
Rats were divided into 5 group: intact VNS, afferent VNS (left VNS in the presence of left caudal vagotomy), efferent VNS (left VNS in the presence of left rostral vagotomy), sham, vagotomy. Rats underwent the implantation of cuff-electrode on left vagus nerve and 6-hydroxydopamine administration into the left striatum simultaneously. Electrical stimulation was delivered just after 6-OHDA administration and continued for 14 days. In afferent VNS and efferent VNS group, the vagus nerve was dissected at distal or proximal portion of cuff-electrode to imitate the selective stimulation of afferent or efferent vagal fiber respectively.
RESULTS
Intact VNS and afferent VNS reduced the behavioral impairments in cylinder test and methamphetamine-induced rotation test, which were accompanied by reduced inflammatory glial cells in substantia nigra with the increased density of the rate limiting enzyme in locus coeruleus. In contrast, efferent VNS did not exert any therapeutic effects.
CONCLUSION
Continuous VNS promoted neuroprotective and anti-inflammatory effect in experimental PD, highlighting the crucial role of the afferent vagal pathway in mediating these therapeutic outcomes.
Topics: Rats; Animals; Parkinson Disease; Vagus Nerve Stimulation; Vagus Nerve; Afferent Pathways; Anti-Inflammatory Agents
PubMed: 36914065
DOI: 10.1016/j.brs.2023.03.003 -
Frontiers in Neuroscience 2021The excitation of vagal mechanoreceptors located in the stomach wall directly contributes to satiation. Thus, a loss of gastric innervation would normally be expected to...
The excitation of vagal mechanoreceptors located in the stomach wall directly contributes to satiation. Thus, a loss of gastric innervation would normally be expected to result in abrogated satiation, hyperphagia, and unwanted weight gain. While Roux-en-Y-gastric bypass (RYGB) inevitably results in gastric denervation, paradoxically, bypassed subjects continue to experience satiation. Inspired by the literature in neurology on phantom limbs, I propose a new hypothesis in which damage to the stomach innervation during RYGB, including its vagal supply, leads to large-scale maladaptive changes in viscerosensory nerves and connected brain circuits. As a result, satiation may continue to arise, sometimes at exaggerated levels, even in subjects with a denervated or truncated stomach. The same maladaptive changes may also contribute to dysautonomia, unexplained pain, and new emotional responses to eating. I further revisit the metabolic benefits of bariatric surgery, with an emphasis on RYGB, in the light of this .
PubMed: 33597843
DOI: 10.3389/fnins.2021.626085 -
Biomarkers in Medicine Jun 2021Parkinson's disease (PD) is a highly prevalent and irreversible neurodegenerative disorder that is typically diagnosed in an advanced stage. Currently, there are no... (Review)
Review
Parkinson's disease (PD) is a highly prevalent and irreversible neurodegenerative disorder that is typically diagnosed in an advanced stage. Currently, there are no approved biomarkers that reliably identify PD patients before they have undergone extensive neuronal damage, eliminating the opportunity for future disease-modifying therapies to intervene in disease progression. This unmet need for diagnostic and therapeutic biomarkers has fueled PD research for decades, but these efforts have not yet yielded actionable results. Recently, studies exploring mechanisms underlying PD progression have offered insights into multisystemic contributions to pathology, challenging the classic perspective of PD as a disease isolated to the brain. This shift in understanding has opened the door to potential new biomarkers from multiple sites in the body. This review focuses on emerging candidates for PD biomarkers in the context of current diagnostic approaches and multiple organ systems that contribute to disease.
Topics: Animals; Biomarkers; Disease Progression; Humans; Parkinson Disease
PubMed: 33988462
DOI: 10.2217/bmm-2020-0654 -
Brain, Behavior, and Immunity Apr 2024The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute...
BACKGROUND
The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN) as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide (LPS, endotoxin) and in mice subjected to cecal ligation and puncture (CLP) sepsis.
METHODS
Anesthetized male 8-10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (500, 250 or 50 μA at 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24 h after CLP. CLP survival was monitored for 14 days.
RESULTS
Either left or right eDMNS at 500 μA and 250 μA decreased HR, compared with baseline pre-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and was not associated with serum corticosterone alterations. Right side eDMNS in endotoxemic mice suppressed serum TNF and increased serum IL-10 levels but had no effects on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice.
CONCLUSIONS
For the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation. These eDMNS anti-inflammatory effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN.
PubMed: 38670240
DOI: 10.1016/j.bbi.2024.04.027 -
Dysphagia Oct 2023Respiratory-related dysphagia and aspiration pneumonia can be attributed to multiple causes. However, reproduction of multiple factor-related respiratory distress and...
Respiratory-related dysphagia and aspiration pneumonia can be attributed to multiple causes. However, reproduction of multiple factor-related respiratory distress and aspiration pneumonia in a single animal model is challenging. To validate animals with vagal nerve palsy as novel models for severe aspiration pneumonia associated with respiratory distress, we investigated the effects of unilateral vagotomy on the swallowing function and severity of pneumonia after forced aspiration in mice. Unilateral vagotomy was performed in C57BL6 male mice that subsequently underwent evaluation of swallowing function by videofluoroscopic swallow study (VFSS) and histological assessments for aspiration pneumonia induced by lipopolysaccharide (LPS). VFSS examinations demonstrated that unilateral vagotomy did not cause apparent aspiration in mice, but it resulted in a significant loss of body weight (BW) due to decreased oral intake. In addition, when aspiration pneumonia was induced by forced administration of LPS, significantly prolonged BW loss and severe infiltration of inflammatory cells associated with aspiration pneumonia were observed in the mice that underwent unilateral vagotomy. In conclusion, the vagotomized mice showed appropriate characteristics as a model of aspiration pneumonia caused by multiple factors, including the paralysis of vocal fold movement and respiratory distress. This model can help elucidate the pathogenesis of aspiration pneumonia and the treatment methods for the respiration-compromised model.
Topics: Male; Animals; Mice; Lipopolysaccharides; Fluoroscopy; Retrospective Studies; Pneumonia, Aspiration; Deglutition; Deglutition Disorders; Paralysis; Respiratory Distress Syndrome
PubMed: 36788140
DOI: 10.1007/s00455-023-10564-3 -
Endocrinologia, Diabetes Y Nutricion 2020Obesity is a prevalent health problem in our population. Bariatric surgery is the indicated treatment for severe cases. It is very effective (together with an adequate... (Review)
Review
Obesity is a prevalent health problem in our population. Bariatric surgery is the indicated treatment for severe cases. It is very effective (together with an adequate lifestyle modification) but it is also associated with frequent adverse events. One of the most frequent and disturbing adverse event is diarrhea. Diarrhea after bariatric surgery may be secondary to multiple causes and the physiopathogenic mechanisms may depend on the type of surgery performed. The most frequent diarrhea mechanisms are dumping syndrome, vagotomy, short bowel syndrome, carbohydrate malabsorption, protein malabsorption, alterations of the microbiota, Clostridium difficile infection, bacterial overgrowth, bile salt malabsorption, pancreatic insufficiency, endocrinological disorders, addictive disorders, and other digestive disorders not necessarily related to surgery.
Topics: Algorithms; Bariatric Surgery; Diarrhea; Humans; Postoperative Complications; Syndrome
PubMed: 31843494
DOI: 10.1016/j.endinu.2019.09.013 -
Toxicological Sciences : An Official... May 2021Air pollution has been associated with metabolic diseases and hepatic steatosis-like changes. We have shown that ozone alters liver gene expression for metabolic...
Air pollution has been associated with metabolic diseases and hepatic steatosis-like changes. We have shown that ozone alters liver gene expression for metabolic processes through neuroendocrine activation. This study aimed to further characterize ozone-induced changes and to determine the impact of hepatic vagotomy (HV) which reduces parasympathetic influence. Twelve-week-old male Wistar-Kyoto rats underwent HV or sham surgery 5-6 days before air or ozone exposure (0 or 1 ppm; 4 h/day for 1 or 2 days). Ozone-induced lung injury, hyperglycemia, glucose intolerance, and increases in circulating cholesterol, triglycerides, and leptin were similar in rats with HV and sham surgery. However, decreases in circulating insulin and increased HDL and LDL were observed only in ozone-exposed HV rats. Ozone exposure resulted in changed liver gene expression in both sham and HV rats (sham > HV), however, HV did not change expression in air-exposed rats. Upstream target analysis revealed that ozone-induced transcriptomic changes were similar to responses induced by glucocorticoid-mediated processes in both sham and HV rats. The directionality of ozone-induced changes reflecting cellular response to stress, metabolic pathways, and immune surveillance was similar in sham and HV rats. However, pathways regulating cell-cycle, regeneration, proliferation, cell growth, and survival were enriched by ozone in a directionally opposing manner between sham and HV rats. In conclusion, parasympathetic innervation modulated ozone-induced liver transcriptional responses for cell growth and regeneration without affecting stress-mediated metabolic changes. Thus, impaired neuroendocrine axes and parasympathetic innervation could collectively contribute to adverse effects of air pollutants on the liver.
Topics: Air Pollutants; Animals; Liver; Male; Ozone; Rats; Rats, Inbred WKY; Transcriptome
PubMed: 33662111
DOI: 10.1093/toxsci/kfab025